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Parasite histones are toxic to brain endothelium and link blood barrier breakdown and thrombosis in cerebral malaria

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posted on 01.07.2021, 13:24 by Christopher A Moxon, Yasir Alhamdi, Janet Storm, Julien M H Toh, Dagmara McGuinness, Joo Yeon Ko, George Murphy, Steven Lane, Terrie E Taylor, Karl B Seydel, Sam Kampondeni, Michael Potchen, James O'Donnell, Niamh O'Regan, Guozheng Wang, Guillermo García-Cardenã, Malcolm Molyneux, Alister G Craig, Simon T Abrams, Cheng-Hock Toh
Microvascular thrombosis and blood-brain barrier (BBB) breakdown are key components of cerebral malaria (CM) pathogenesis in African children and are implicated in fatal brain swelling. How Plasmodium falciparum infection causes this endothelial disruption and why this occurs, particularly in the brain, is not fully understood. In this study, we have demonstrated that circulating extracellular histones, equally of host and parasite origin, are significantly elevated in CM patients. Higher histone levels are associated with brain swelling on magnetic resonance imaging. On postmortem brain sections of CM patients, we found that histones are colocalized with P falciparum-infected erythrocytes sequestered inside small blood vessels, suggesting that histones might be expelled locally during parasite schizont rupture. Histone staining on the luminal vascular surface colocalized with thrombosis and leakage, indicating a possible link between endothelial surface accumulation of histones and coagulation activation and BBB breakdown. Supporting this, patient sera or purified P falciparum histones caused disruption of barrier function and were toxic to cultured human brain endothelial cells, which were abrogated with antihistone antibody and nonanticoagulant heparin. Overall, our data support a role for histones of parasite and host origin in thrombosis, BBB breakdown, and brain swelling in CM, processes implicated in the causal pathway to death. Neutralizing histones with agents such as nonanticoagulant heparin warrant exploration to prevent brain swelling in the development or progression of CM and thereby to improve outcomes.

Funding

Wellcome Trust (109698/Z/15/Z)

Academy of Medical Sciences

National Institutes of Health, National Institute of Allergy and Infectious Diseases (5R01AI034969-14)

British Heart Foundation (PG/14/19/30751 and PG/16/65/32313)

Wellcome Trust (084679/Z/08/Z)

Wellcome Trust (104111)

History

Comments

This research was originally published in Blood Advances. Author(s). Moxon CA, Alhamdi Y, Storm J, Toh JMH, McGuinness D, Ko JY, Murphy G, Lane S, Taylor TE, Seydel KB, Kampondeni S, Potchen M, O'Donnell JS, O'Regan N, Wang G, García-Cardeña G, Molyneux M, Craig AG, Abrams ST, Toh CH. Parasite histones are toxic to brain endothelium and link blood barrier breakdown and thrombosis in cerebral malaria. Blood Adv. 2020;4(13):2851-2864. © the American Society of Hematology.

Published Citation

Moxon CA, Alhamdi Y, Storm J, Toh JMH, McGuinness D, Ko JY, Murphy G, Lane S, Taylor TE, Seydel KB, Kampondeni S, Potchen M, O'Donnell JS, O'Regan N, Wang G, García-Cardeña G, Molyneux M, Craig AG, Abrams ST, Toh CH. Parasite histones are toxic to brain endothelium and link blood barrier breakdown and thrombosis in cerebral malaria. Blood Adv. 2020;4(13):2851-2864.

Publication Date

24 June 2020

PubMed ID

32579667

Department/Unit

  • Irish Centre for Vascular Biology
  • School of Pharmacy and Biomolecular Sciences

Research Area

  • Vascular Biology

Publisher

American Society of Hematology

Version

  • Published Version (Version of Record)